Cytogenetic Response to Treatment Correlates With Long-Term Survival of Patients With Acute Myeloid Leukemia

Patients with acute myeloid leukemia (AML) who maintain normal cytogenetics (Cy) after initial treatment have a significantly higher probability of 12-month overall survival compared with those with ongoing or newly acquired cytogenetic abnormalities, according to a recent study. Complete or partial Cy normalization is also highly associated with improved overall survival, regardless of whether patients have a normal karyotype at baseline. These findings were published in the American Journal of Hematology.

This is the first study to refine the categorization of altered cytogenetics at time of response assessment and analyze their impact on patient outcomes. “Clinicians often monitor minimal residual disease, but it’s hard to make meaningful conclusions from these measurements in patients with AML,” says study senior author Moaath K. Mustafa Ali, MD, a medical oncologist at Cleveland Clinic Cancer Institute. “Understanding the implications of persistence or changes in cytogenetic abnormalities at the time of response would allow for a more comprehensive assessment.”

Background

Detailed prognostic systems already exist for AML. However, there has been little understanding of how abnormal cytogenetics at baseline were impacted by treatment, or how changes in cytogenetics affected a patient’s prognosis. To date, cytogenetics has been evaluated at the time of response and classified in a binary way, either as abnormal or normal. There was no distinction between complete or partial clearance of abnormalities or changes in the abnormalities themselves.

Thus, researchers were looking to improve upon Cy response assessment – and to understand the prognostic value of cytogenetic alterations.

Classification system refinement

When Dr. Mustafa Ali joined the Cleveland Clinic, he worked alongside Director of Molecular Pathology & Cytogenomics Caroline Astbury, PhD, FACMG, to establish a database to track patients’ Cy response after initial treatment for AML. “We changed the classification from qualitative to quantitative to account for variations in response,” says Dr. Astbury.

Together, they made the response classification system more granular, identifying patients by:

• Complete Cy remission – All cytogenetic abnormalities present at baseline had disappeared
• Partial Cy remission – Abnormalities improved by at least 50%
• Persistent Cy abnormalities – Abnormalities that existed at baseline were still present
• Gain in Cy abnormalities – Acquisition of new cytogenetic abnormalities

Study design

Nine hundred seventy-three adult patients with AML were treated at the Cleveland Clinic between January 2015 and September 2023. Of those, the researchers were able to retrospectively analyze 563 patients. At baseline, 41% of the patients had a normal karyotype and 59% had abnormal cytogenetics.

At the 60-day landmark after initial treatment, 39% of patients had retained normal cytogenetics, 35% had a complete Cy response, 3.6% had a partial Cy response, 14% had ongoing Cy abnormalities, and 8.2% had newly gained Cy abnormalities. The researchers then correlated these cytogenetic changes with the probability of overall survival (OS). The median follow-up was 45.8 months.

Study results

Patients who maintained normal cytogenetics had a 12-month OS probability of 73% compared to patients with ongoing or new cytogenetic abnormalities, who had a 12-month OS probability of 53%. Notably, patients who achieved a partial Cy response had survival outcomes comparable to those with a complete Cy response. “This analysis shows that patients with a partial Cy response may not have increased risk of mortality or refractory disease,” says Dr. Mustafa Ali. “In fact, their prognosis is similar to those with a complete Cy remission.”

The study also highlights the fact that newly acquired or persistent cytogenetic abnormalities reduce the odds of long-term survival, even among patients who underwent a stem cell transplant. “In my opinion, the persistence or gain of cytogenetic abnormalities is generally a sign to change to a regimen with a different mechanism of action,” says Dr. Mustafa Ali. He notes that validation of the findings is needed before incorporating them into AML response criteria.